BRPI0411904B1 - inhalable formulations for the treatment of pulmonary hypertension - Google Patents

Abstract

The present invention is directed to an inhalable formulation for the treatment of pulmonary hypertension in a mammal (e.g., humans), wherein the formulation comprises at least one hypertension reducing agent, including but not limited to an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, calcium-channel blocker or vasodilator, or any combination thereof. The formulations of the present invention may be a solution or suspension, and preferably are suitable for administration via nebulization. The present invention is also directed to a method and kit for treating a mammal suffering from pulmonary hypertension.

Description

I. FIELD OF THE INVENTION

[001] The present invention relates to an inhalable formulation for the treatment of pulmonary hypertension and processes for treating it in mammals, including humans. The formulation of the present invention comprises a hypertension-reducing agent, wherein the hypertension-reducing agent can include an angiotensin-converting enzyme inhibitor ("ACEI"), angiotensin-receptor blocking agent ("ARB"), beta-adrenergic blocking agent ("beta-blockers"), calcium channel blocker or vasodilator or any combination thereof. Preferably, the formulation of the present invention is suitable for administration by nebulization. The present invention also relates to a pre-packaged kit for the treatment of pulmonary hypertension that contains the formulation of the present invention.

II. BACKGROUND OF THE INVENTION

[002] Pulmonary hypertension is a disorder of the lung in which the pressure in the pulmonary artery (the blood vessel that leads from the heart to the lungs) rises above normal levels. Left untreated, pulmonary hypertension can become life-threatening. Symptoms of pulmonary hypertension include poor breathing with minimal effort, fatigue, chest pain, fainting, dizziness attacks and other symptoms. Pulmonary hypertension is often misdiagnosed and has often progressed to a later stage at the time it was diagnosed. In addition, pulmonary hypertension has historically been chronic and incurable with a low survival rate.

[003] When pulmonary hypertension occurs in the absence of a known cause, it is called primary pulmonary hypertension (PPH). There are many unknown causes of PPH.

[004] When the cause of pulmonary hypertension is known, it is called secondary pulmonary hypertension (SPH). The common causes of SPH are emphysema, bronchitis and chronic obstructive pulmonary disorders, among others. Other less frequent causes are inflammatory or vascular collagen diseases such as scleroderma, CREST syndrome or systemic lupus erythematosus. Congenital heart diseases that cause the diversion of extra blood through the lungs such as ventricular and arterial septal defects, chronic pulmonary thromboembolism (old blood clots in the pulmonary artery), HIV infection, liver disease and diet drugs like fenfluramine and dexfenfluramine also are causes of pulmonary hypertension.

[005] Angiotensin converting enzyme inhibitors (ACEI) are drugs used to treat hypertension (high blood pressure) and congestive heart failure. These drugs are also used to relieve tension about hearts damaged by heart attacks. ACEIs block the production of an enzyme that helps convert the protein angiotensin I into angiotensin II, a protein that restricts blood vessels and promotes fluid retention in the body, thereby raising blood pressure. ACEIs also cause blood vessels to relax, which helps to lower blood pressure and allows the oxygen-rich blood to reach the heart. Captorpril (Capoten), Ramipril (Altace and Enalipril (Vasoted)) are commonly used ACE inhibitors.

[006] Angiotensin receptor blockers (ARBs) (also called angiotensin II receptor agonists) such as losartan (Cozaar) and valsartan (Diovan) reduce hypertension by displacing angiotensin II receptors on the cell surface. ARBs are used as alternatives to less expensive ACEI inhibitors because they have less side effects.

[007] Beta-adrenergic blocking agents or beta-blockers are used to treat high blood pressure. Beta-blockers are also used for the relief of angina (chest pain) and in patients with heart attacks to help prevent additional heart attacks. Beta-blockers are also used to correct irregular heartbeats, prevent migraines and treat tremors. Beta-blockers are competitive inhibitors and interfere with the action of stimulating hormones on beta-adrenergic receptors in the nervous system. Beta-blockers can be subdivided into two distinct groups, known as beta-1 and beta-2. Beta-1 blockers mainly affect the heart and beta-2 blockers mainly affect bronchial tissue. Most beta-blockers are non-specific, that is, they have both beta-1 and beta-2 effects.

[008] Calcium channel blockers are currently used to control hypertension, chest pain and irregular heartbeat. Calcium channel blockers slow the rate at which calcium passes to the heart muscle and vessel walls, thereby relaxing the vessels. Relaxed vessels let blood flow through them more easily, thereby lowering blood pressure.

[009] Vasodilators are drugs that act directly on muscles in the walls of blood vessels to make blood vessels larger (dilate). Vasodilators are used to treat high blood pressure. By enlarging the arteries, these drugs allow the blood to drain more easily, reducing blood pressure. Controlling high blood pressure is important because the condition places a burden on the heart and arteries, which can lead to permanent damage over time. If left untreated, high blood pressure increases the risk of heart attacks, heart failure, stroke or kidney failure. Examples of vasodilators include prostacyclin and its analogs.

[0010] Vasodilators such as prostacyclin and prostacyclin analogues as well as calcium channel blockers such as diltiazem (Cardizem) or nifedipine (procardia) have been shown to decrease pulmonary vascular resistance in some patients when administered systemically. For example, a continuous intravenous infusion of the vasodilator epoprostenol (Flolan) or prostacyclin has been found to improve exercise capacity, quality of life, hemodynamics and long-term survival in patients with primary pulmonary hypertension. Epoprostenol is a potent fast-acting vasodilator and inhibitor of platelet aggregation by vascular endothelium.

[0011] Continuous intravenous prostacyclin is far from ideal as a treatment for pulmonary hypertension, however, since the agent is only available in limited supply, it is very expensive and optimal control requires that intravenous prostacyclin therapy be started in centers specialists familiar with the technique, the equipment and the dosage range. In addition, continuous intravenous administration of prostacyclin results in significant side effects in patients, including jaw pain, nausea and anorexia, in addition to the potential inconvenience and danger from prolonged catheterization and ruptures in the delivery system. In addition, since the agent is applied systemically with only a small percentage of the agent actually absorbed by the pulmonary system, it must be administered in high doses.

[0012] Epoprostenol or the prostacyclin analogue, treprostinil sodium can be administered by injection to treat pulmonary hypertension. The application, however, is systemic and not located in the lung. Thus, the drug should be administered in high doses, with only a small percentage that actually reaches the lungs.

[0013] It has also been shown that calcium channel blockers can relieve pulmonary vasoconstriction and prolong life in approximately 20 percent of patients with PPH. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76-81, which is incorporated herein by reference. In patients who present evidence of an acute hemodynamic response; long-term treatment with orally administered calcium channel blockers can produce a prolonged hemodynamic response and increase survival. However, oral administration does not have a localized effect on the lungs and therefore high doses should be administered, producing a systemic effect, perhaps unnecessarily. In addition, oral administration in high doses over an extended period of time may produce unwanted side effects in some patients.

[0014] There is, however, a need for an improved process for treating hypertension.

III. SUMMARY OF THE INVENTION

[0015] The formulations provided here are used to treat, prevent and / or ameliorate one or more symptoms of a condition, disorder or disease. As used in this case, treatment means any way in which one or more of the symptoms of the condition, disorder or disease is improved or else advantageously altered. The treatment also covers any pharmaceutical or medicinal use of the formulations in this case. As used in this case, ameliorating the symptoms of a particular disorder by administering a particular formulation refers to any decrease, whether permanent or temporary, lasting or transient that can be attributed to or associated with the administration of the formulation. As used in this case, an "effective therapeutic amount" means a sufficient amount of the drug substance to treat, prevent and / or ameliorate one or more symptoms of a medical condition, disorder or disease. It may also include a safe and tolerable amount of the drug substance, as based on industry and / or regulatory standards.

[0016] In an alternative embodiment, the formulations provided here are used for the treatment, prevention and / or amelioration of one or more symptoms of a respiratory disorder in an individual. In another alternative embodiment, the present invention provides a formulation for the treatment, prophylaxis and / or amelioration of one or more symptoms of pulmonary hypertension or other related disorders.

[0017] In a preferred embodiment, the present invention provides a formulation for the treatment of pulmonary hypertension in a mammal (e.g., humans), wherein the formulation is suitable for administration through inhalation. Preferably, the formulation of the present invention is suitable for administration by nebulization. The formulations of the present invention comprise a therapeutically effective amount of a hypertension reducing agent. Hypertension reducing agents suitable for use in the present formulations include, ACEI, ARBs, beta-blockers, calcium channel blockers or vasodilators or any combination thereof. In an alternative embodiment, the formulation of the present invention comprises a combination of two or more hypertension reducing agents.

[0018] The formulations of the present inventions can be supplied as a solution or as an aqueous suspension, provided that the formulation is suitable for inhalation. Preferably, the present formulation is sterile. In another embodiment, the formulation of the present invention is stable. In addition, buffering agents can be added to adjust the pH level of the formulation. In addition, the formulations of the present invention may contain an antimicrobial preservative. Alternatively, the formulations in this case may be free of preservatives. In one embodiment, the formulations of the present invention are suitable for the treatment and diagnosis or level of pulmonary hypertension.

[0019] The present invention also relates to a method for the treatment of pulmonary hypertension in a mammal, which includes animals or humans. In one embodiment, the method of the present invention comprises the step of administering the formulation of the present invention to a mammal in need thereof. In one embodiment, the method of the present invention further comprises the step of administering another therapy or a pharmaceutical agent useful or related to the treatment of pulmonary hypertension. Such therapies and / or pharmaceutical agents including, for example, anticoagulants and diuretics.

[0020] Additionally, the present invention is directed to a kit for the treatment of pulmonary hypertension in a mammal. In one embodiment, the kit of the present invention comprises the formulation of the present invention. In another embodiment, the kit formulation is pre-measured, pre-mixed and pre-packaged. In an alternative embodiment, the kit also includes instructions for administering the formulation.

[0021] Other modalities, characteristics and advantages of the present invention will be evident to those skilled in the art in view of the following detailed description of the invention.

IV. DETAILED DESCRIPTION OF THE INVENTION

[0022] As used in this case, the terms "angiotensin-converting enzyme inhibitor" or "ACEI" mean any pharmaceutical agent that inhibits the enzymatic activity of the angiotensin-converting enzyme. ACEIs suitable for use in this case include, but are not limited to, Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Trandolapril and prodrugs, salts and isomers thereof.

[0023] As used in this case, the terms "angiotensin receptor blocker" or "ARB" or "angiotensin II receptor agonist" mean any pharmaceutical agent that selectively blocks the binding of angiotensin II to receptors found in many tissues. ARBs suitable for use in this case include, but are not limited to, Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan and prodrugs, salts and isomers thereof.

[0024] As used in this case, the terms "beta-adrenergic blocking agent" or "beta-blocker" mean any pharmaceutical agent that blocks beta-adrenergic substances in the body. For example, a beta-blocker can block the beta-adrenergic substance adrenaline (epinephrine), a key agent in the "comprehensive" part of the autonomic (involuntary) nervous system and activation of the heart muscle. Beta-blockers suitable for use in this case include, but are not limited to, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Esmolol, Labetalol, Metoprolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Solol and Timolol -drugs, salts and isomers thereof.

[0025] As used in this case, the term "calcium channel blocker" means any pharmaceutical agent that slows or blocks the entry of calcium into muscle cells in the heart and arteries. Suitable calcium channel blockers for use in this case include, but are not limited to, Amlodipine, Bepridil, Diltiazem, Felodipine, Flunarizine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Verapamil and prodrugs, salts and isomers thereof.

[0026] As used in this case, the term "vasodilator" means any pharmaceutical agent that causes the dilation of blood vessels. Vasodilators suitable for use in this case include, but are not limited to, Adenine, Arginine, Doxazosin, Hydralazine Hydrochloride, Isosorbide

[0027] Initrate, Isosorbide Mononitrate Minoxidil, Nicotinates, Nitroglycerin, Phentolamine, Prazosin, Terazosin and prodrugs, salts and isomers thereof. Vasodilators for use in this case also include prostaglandins (Eicosanoids), including prostacyclin (Epoprostenol) and prostacyclin analogues, including

[0028] lloprost and Treprostinil and prodrugs, salts and isomers thereof. Also included in this case are the various prostaglandins, which include but are not limited to PGE-1; PGE-2; PGF-2.alpha; PGA-1; PGB-1; PGD-2; PGE-M; PGF-M; PGH-2; PGI-2;

[0029] 19-hydroxy-PGA-1; 19-hydroxy-PGB-1; PGA-2; PGB-2; 19-hydroxy-PGA-2; 19-hydroxy-PGB-2; PGB-3; PGF-1.alpha .; 15-methyl-PGF- 2.alpha .; 16,16-dimethyl-.DELTA..sup.2 -PGE-1 methyl ester; 15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester; 16,16-dimethyl-PGE-2; 11-deoxy-15-methyl-PGE-1; 16-methyl-18,18,19,19-tetrahydrocarbacycline; (16RS) -15-deoxy-16-hydroxy-16-methyl-PGE-1 methyl ester; (+) -

[0030] 4,5-didhydro-16-phenoxy-alpha-tetranor-PGE-2 methyl ester; 11-deoxy-11a, 16,16-trimethyl-PGE-2; (+) - 11 a, 16a, b-dihydroxy-1,9-dioxo-1- (hid roxi methyl) -16-methyl-trans-prosthesis; 9-chloro-16,16-dimethyl-PGE-2; arboprostil; iloprost; CL 15.347: and semi-synthetic and synthetic derivatives of natural prostaglandins or any derivative or any prostaglandin analogue capable of acting as a vasodilator and prodrugs, salts and isomers thereof.

[0031] As used in this case, the term "hypertension-reducing pharmaceutical agent" means any ACEI, ARB, beta-blocker, calcium channel blocker, vasodilator or any other compound capable of treating pulmonary hypertension through oral inhalation, such like fogging. It is understood that the list of hypertension reducing agents above includes those not currently approved for use in clinical practice in the United States and those that will be approved in the future.

[0032] As used in this case, the term "pulmonary hypertension" means any form, diagnosis, level or stage of pulmonary hypertension, including, but not limited to, primary or secondary pulmonary hypertension, pulmonary arterial hypertension, venous pulmonary hypertension, associated pulmonary hypertension with respiratory system disorders or hypothermia, pulmonary hypertension resulting from chronic thrombotic or embolic disease or pulmonary hypertension resulting from disorders that directly affect the pulmonary vasculature. The term "pulmonary hypertension" also includes other respiratory disorders characterized by acute pulmonary vasoconstriction such as those resulting from pneumonia, traumatic damage, aspiration or inhalation damage, fatty embolism in the lung, inflammation due to lung acidosis, respiratory distress syndrome adult, acute pulmonary edema, acute mountain malaise, post-cardiac surgery, acute pulmonary hypertension, newborn persistent pulmonary hypertension, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protomine reactions, septicemia, asthmatic states or hypoxia (including iatrogenic hypoxia) and other forms of reversible vasoconstriction. Such lung disorders are also characterized by inflammation of the lung including those associated with the migration to the lung of non-resident cell types including the various leukocyte subclasses.

[0033] In an alternative embodiment, the formulations of the present invention can include derivatives of a pharmaceutically acceptable hypertension reducing agent. As used in this case, derivatives of such pharmaceutically acceptable compounds include, but are not limited to, salts, esters, enol ethers, enol esters, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives can be readily prepared by those skilled in the art using known methods for such derivatization. Such derivatives produced can be administered to animals or humans without substantial toxic effects.

Suitable "pharmaceutically acceptable salts" include conventionally used non-toxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt), an alkali metal salt earthy (such as calcium salt and magnesium salt), an ammonium salt or a salt with an organic base, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, salt of benzylamine, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethyl monoethanolamine salt, procaine salt and caffeine salt), a basic amino acid salt (such as arginine salt and lysine salt), tetraalkyl ammonium salt and the like or other form of salt that allows the pulmonary hypertension reducing agent to remain soluble in a liquid medium or to be prepared and / or effectively administered in a liquid medium , preferably in an aqueous medium. The above salts can be prepared by a conventional process, for example starting from the corresponding acid and base or by an exchange with salt.

[0035] For example, an alternative modality, the hypertension reducing agent can be used in a gaseous form or in a salt form (for example, as pharmaceutically acceptable salts). Examples of pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; organic acid addition salts such as acetate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate and ascorbate; salts with acidic amino acids such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; organic-based salt such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt and N, N'-dibenzylethylenediamine salt and salts with basic amino acid such as lysine salt and arginine salt. The salts may in some cases be ethanol hydrates or solvates.

[0036] Examples of ethers may include, but are not limited to, alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl ether and 1-cyclopropyl ethyl ether and medium or higher alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such as oleyl ether and linolenyl ether; alkenyl lower ethers such as vinyl ether, allyl ether; alkynyl lower ethers such as ethynyl ether and propynyl ether; hydroxy (lower) alkyl ethers such as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy (lower) alkyl ethers such as methoxymethyl ether and 1-methoxyethyl ether; aryl optionally substituted ethers such as phenyl ether, tosyl ether, t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and benzamidophenyl ether; and aryl (lower) alkyl ethers such as benzyl ether, trityl ether and benzhydryl ether or other forms of ether that allow the pulmonary hypertension reducing agent to remain soluble in a liquid medium or to be prepared and / or effectively administered in a liquid medium, preferably in an aqueous medium.

[0037] Examples of the esters may include, but are not limited to, aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester and allyl ester; alkynyl lower esters such as ethynyl ester and propynyl ester; hydroxy (lower) alkyl ester such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such as methoxymethyl ester and 1-methoxyethyl ester and optionally substituted aryl esters such as, for example, phenyl ester, tosyl ester, t-butylphenyl ester, salicylyl ester, 3,4-di-methoxyphenyl ester and benzamidophenyl ester; and aryl (lower) alkyl ester such as benzyl ester, trityl ester and benzhydryl ester or other forms of ester that allow the hypertension reducing agent to remain soluble in a liquid medium or to be prepared and / or effectively administered in a liquid medium, preferably in an aqueous medium.

[0038] In addition, the hypertension-reducing agent for use in the formulations and processes provided here may contain chiral centers. Such chiral centers may be of (R) or (S) configuration or may be a mixture thereof. Thus, the compounds for use in the formulations provided herein can be enanciomerically pure or they can be stereoisomeric or diastereomeric mixtures. It should be understood that the chiral centers of the compounds provided herein can undergo epimerization in vivo. Thus, one skilled in the art will recognize that the administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to the administration of the compound in its (S) form.

[0039] The present invention provides an inhalable formulation for the treatment of pulmonary hypertension, wherein the formulation comprises a therapeutically effective amount of a hypertension reducing agent for the treatment of pulmonary hypertension in which the hypertension reducing agent is an ACEI, a ARB, a beta-blocker, a calcium channel blocker or a vasodilator or any combination thereof.

[0040] The present invention is based, in part, on the known systemic reducing effects on hypertension of ACEIs, ARBs, beta-blockers, calcium channel blockers or vasodilators to treat pulmonary hypertension. It is believed that the formulations of the present invention represent an improvement over conventional means for the treatment of pulmonary hypertension because the application of the hypertension reducing agent would be located in the pulmonary system of the user, as opposed to the systemic application. It is believed that localized therapy may increase bioavailability as well as its increased efficiency and / or the prolonged therapeutic effect. Because of the greater bioavailability, the present formulations may contain lower dosages of hypertension reducing agents while effectively treating pulmonary hypertension. Additionally, it is believed that localized therapy may result in a decrease in side effects due to lower dosages and a decrease in patient discomfort and inconvenience due to the less invasive or time-consuming systemic application method.

[0041] In a embodiment of the present invention, a therapeutically effective amount of a hypertension reducing agent can include from approximately 0.001 mg / mL to approximately 20 mg / mL of an ACEI, an ARB, a beta-blocker, a channel blocker calcium, a vasodilator or any combination thereof. In an alternative embodiment, a therapeutically effective amount of a hypertension-reducing agent can include from approximately 0.008 mg / ml to approximately 15.0 mg / ml. It can also include the following intermediate ranges approximately 0.001 mg / mL to approximately 0.50 mg / ml approximately 0.51 mg / mL to approximately 1.00 mg / ml approximately 1.01 mg / mL to approximately 1.50 mg / mL ml approximately 1.51 mg / ml up to approximately 2.00 mg / ml approximately 2.51 mg / ml up to approximately 3.00 mg / ml approximately 3.01 mg / ml up to approximately 3.50 mg / ml approximately 3.51 mg / ml to approximately 4.00 mg / ml to approximately 4.01 mg / ml to approximately 4.50 mg / ml to approximately 4.51 mg / ml to approximately 5.00 mg / ml to approximately 5.01 mg / ml to approximately 5.50 mg / ml approximately 5.51 mg / ml to approximately 6.00 mg / ml approximately 6.01 mg / ml to approximately 6.50 mg / ml approximately 6.51 mg / ml to approximately 7.00 mg / ml approximately 7.01 mg / ml to approximately 7.50 mg / ml approximately 7.51 mg / ml to approximately 8.00 mg / ml approximately 8.01 mg / ml to approximately 8.50 mg / ml approximately between 8.51 mg / ml up to approximately 9.00 mg / ml approximately 9.01 mg / ml up to approximately 9.50 mg / ml approximately 9.51 mg / ml up to approximately 10.00 mg / ml approximately 10.01 mg / ml up to approximately 10.50 mg / ml approximately 10.51 mg / ml up to approximately 11.00 rng / ml approximately 11.01 mg / ml up to approximately 11.50 mg / ml approximately 11.50 mg / ml up to approximately 12 , 00 mg / ml approximately 12.00 mg / ml to approximately 12.51 mg / ml approximately 12.51 mg / ml to approximately 13.00 mg / ml approximately 13.01 mg / ml to approximately 13.50 mg / ml approximately 13.51 mg / ml to approximately 14.00 mg / ml approximately 14.01 mg / ml to approximately 14.50 mg / ml approximately 14.51 mg / ml to approximately 15.00 mg / ml.

[0042] In an alternative embodiment of the present invention, a therapeutically effective amount of a hypertension reducing agent can include the following intermediate ranges: approximately 0.001 mg / ml to approximately 1.0 mg / ml; approximately 0.005 mg / ml to approximately 1.0 mg / ml; approximately 0.01 mg / ml to approximately 1.0 mg / ml; approximately 0.05 mg / ml to approximately 0.1 mg / ml; approximately 0.05 mg / ml to approximately 0.5 mg / ml.

[0043] In another alternative embodiment of the present invention, a therapeutically effective amount of a hypertension reducing agent can include from approximately 0.001 to approximately 10 mg / ml of a hypertension reducing agent, including the following intermediate amounts: approximately 0.001 mg / ml to approximately 1.25 mg / ml; approximately 1.25 mg / mL to approximately 1.50 mg / mL; approximately 1.50 mg / ml to approximately 1.75 mg / ml; approximately 1.75 mg / mL to approximately 2.00 mg / mL; approximately 2.0 mg / ml to approximately 2.25 mg / ml; approximately 2.25 mg / ml to approximately 2.50 mg / ml; approximately 2.50 mg / ml to approximately 2.75 mg / ml; approximately 2.75 mg / ml to approximately 3.00 mg / ml; approximately 3.0 mg / ml to approximately 3.25 mg / ml; approximately 3.25 mg / ml to approximately 3.50 mg / ml; approximately 3.50 mg / mL to approximately 3.75 mg / mL; approximately 3.75 mg / ml to approximately 4.00 mg / ml; approximately 4.0 mg / ml to approximately 4.25 mg / ml; approximately 4.25 mg / ml to approximately 4.50 mg / ml; approximately 4.50 mg / ml to approximately 4.75 mg / ml; approximately 4.75 mg / ml to approximately 5.00 mg / ml; approximately 5.0 mg / ml to approximately 5.25 mg / ml; approximately 5.25 mg / ml to approximately 5.50 mg / ml; approximately 5.50 mg / mL to approximately 5.75 mg / mL; approximately 5.75 mg / ml to approximately 6.00 mg / ml; approximately 6.0 mg / ml to approximately 6.25 mg / ml; approximately 6.25 mg / ml to approximately 6.50 mg / ml; approximately 6.50 mg / ml to approximately 6.75 mg / ml; approximately 6.75 mg / ml to approximately 7.00 mg / ml; approximately 7.0 mg / ml to approximately 7.25 mg / ml; approximately 7.25 mg / ml to approximately 7.50 mg / ml; approximately 7.50 mg / ml to approximately 7.75 mg / ml; approximately 7.75 mg / ml to approximately 8.00 mg / ml; approximately 8.0 mg / ml to approximately 8.25 mg / ml; approximately 8.25 mg / ml to approximately 8.50 mg / ml; approximately 8.50 mg / ml to approximately 8.75 mg / ml; approximately 8.75 mg / ml to approximately 9.00 mg / ml; approximately 9.0 mg / ml to approximately 9.25 mg / ml; approximately 9.25 mg / ml to approximately 9.50 mg / ml; approximately 9.50 mg / ml to approximately 9.75 mg / ml; approximately 9.75 mg / ml to approximately 10.00 mg / ml.

[0044] In one embodiment, the formulation of the present invention is an inhalable solution that comprises a therapeutically effective amount of a pulmonary hypertension agent. Preferably, the inhalable solution of the present invention is suitable for administration via nebulization. The formulations of the present invention can also be provided as an aqueous suspension. In one embodiment, the formulation of the present invention comprises a therapeutically effective amount of a pulmonary hypertension reducing agent in an aqueous suspension.

[0045] The formulations provided herein may comprise any pharmacologically suitable fluid that is physiologically acceptable for administration, including, but not limited to water, aqueous saline solutions with one or more pharmaceutically acceptable salt (salts), alcohols, glycols or any mixture thereof. In one embodiment, the formulation of the present invention comprises water. The water for use in the present formulations should meet or exceed the regulatory requirements applicable for use in inhaled drugs. The specifications established by the United States Pharmacopoeia for "Sterile Water for Injection" or "Sterile Water for Inhalation" ("Sterile Water for Injection" or "Sterile Water for Inhalation") are examples of water suitable for use to prepare the formulations of the invention.

[0046] In an alternative embodiment, the formulation of the present invention can comprise a preservative, a suspending agent, a humidifying agent, a tonicity agent and / or a diluent. The formulations provided herein may comprise from approximately 0.01% to approximately 90%, or approximately 0.01% to approximately 50%, or approximately 0.01% to approximately 25%, or approximately 0.01% to approximately 10%, or approximately 0.01% to approximately 5% of one or more pharmacologically suitable suspension fluids that are physiologically acceptable for intranasal administration. Pharmacologically suitable fluids for use in this case include, but are not limited to, polar solvents, inclusive, but are not limited to compounds containing hydroxyl groups or other polar groups. Solvents include, but are not limited to, water or alcohols, such as ethanol, isopropanol and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene alcohols. Polar solvents also include protic solvents, but are not limited to water, aqueous saline solutions with one or more pharmaceutically acceptable (acceptable) salt (salts), alcohols, glycols or a mixture thereof. In an alternative embodiment, the water for use in the present formulations should meet or exceed the regulatory requirements applicable for use in inhaled drugs.

[0047] Sterility or adequate antimicrobial preservation can be provided as part of the present formulations. As certain formulations of the present invention are intended to be administered orally, it is preferable that they are free of pathogenic organisms. An advantage of a sterile liquid suspension is that it reduces the possibility of introducing contaminants into the individual when the suspension formulation is administered nasally, thereby reducing the chance of an opportunistic infection. The processes that can be considered to achieve sterility can include any appropriate sterilization steps known in the art. In one embodiment, the drug substance (for example, fluticasone) is produced under sterile conditions, micronization is performed in a sterile environment and mixing and packaging are carried out under sterile conditions. In an alternative embodiment, the formulations of the present invention can be filtered sterile and placed in small bottles, including small unit-dose bottles that are used in a nasal spray device. For example, each small unit-dose bottle can be sterile and properly administered without contaminating other small bottles or the next dose. In an alternative embodiment, one or more ingredients of the present formulation can be sterilized by water vapor, gamma radiation or prepared using or mixing sterile steroid powder and other sterile ingredients when appropriate. In addition, formulations can be prepared and handled under sterile conditions or can be sterilized before or after packaging.

[0048] In addition to or in place of sterilization, the formulations of the present invention may contain a pharmaceutically acceptable preservative to minimize the possibility of microbial contamination. In addition, a pharmaceutically acceptable preservative can be used in the present formulations to increase the stability of the formulations. It should be noted, however, that any preservative should be chosen for safe inhalation, as treated tissues may be sensitive to irritating agents. Preservatives suitable for use in this case include, but are not limited to, those that protect the solution against contamination with pathogenic particles, including phenylethyl alcohol, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate and phenylethyl alcohol. Preferably, the preservative for use in the present formulations is benzalkonium chloride. In certain embodiments, the formulations herein comprise from approximately 0.001% to approximately 10.0% by weight / weight of benzalkonium chloride or from approximately 0.01% by weight / weight of phenylethyl alcohol. Preservative agents can also be present in an amount of from approximately 0.001% to approximately 1%, preferably approximately 0.002% to approximately 0.02%, more preferably 0.02% by weight / weight.

[0049] The formulations provided herein may also comprise from approximately 0.001% to approximately 90%, or approximately 0.001% to approximately 50%, or approximately 0.001% to approximately 25%, or approximately 0.001% to approximately 10%, or approximately 0.001% up to approximately 1% of one or more of emulsifying agent, wetting agent or suspending agent. Such agents for use in this case include, but are not limited to, fatty esters of polyoxyethylene sorbitan or polysorbates, inclusive, but are not limited to polyethylene sorbitan monooleate (polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; tragacanth gum; acacia; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose; methylcellulose; hydroxypropylcellulose; hydroxypropylmethylcellulose; ethylmethylcellulose; carboxymethylcellulose; sodium, potassium and calcium salts of fatty acids; mono- and di-glycerides of fatty acids; esters of acetic acid of mono- and di-glycerides of fatty acids; lactic acid esters of mono- and di-glycerides of fatty acids; esters of citric acid of mono- and di-glycerides of fatty acids; esters of tartaric acid of mono- and di-glycerides of fatty acids; esters of mono- and diacetyltartaric acid of mono- and di-glycerides of fatty acids; esters of mixed acetic and tartaric acids of mono- and di-glycerides of fatty acids; sucrose esters of fatty acids; sucroglycerides; polyglycerol esters of fatty acids; polyglycerol esters of polycondensated fatty acids from castor oil; propane-1,2-diol fatty acid esters; sodium stearoyl-2-lactylate; calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; chilaia extract; polyglycerol esters of soybean oil dimerized fatty acids; oxidatively polymerized soybean oil; and pectin extract.

[0050] The present formulations can further comprise from approximately 0.001% to approximately 1% of one or more excipients and additives that are pharmacologically suitable. Excipients and additives generally have pharmacological activity or at least no undesirable pharmacological activity. The concentration of these can vary with the selected agent, although the presence or absence of these agents or their concentration is not an essential aspect of the invention. Excipients and additives may include, but are not limited to, surfactants, moisturizers, stabilizers, complexing agents, antioxidants or other additives known in the art. Complexing agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as disodium salt, citric acid, nitrilotriacetic acid and the salts thereof. In another embodiment, particularly in the suspension formulations provided herein, the complexing agent is sodium edetate. In one mode; the compositions contain sodium edetate at a concentration of approximately 0.05 mg / ml to approximately 0.5 mg / ml, or approximately 0.1 mg / ml to approximately 0.2 mg / ml. In addition, for example, the formulations of the present invention can comprise from approximately 0.001% to approximately 5% by weight of a humectant to inhibit drying of the mucous membrane and to prevent irritation. Any of a variety of pharmaceutically acceptable humectants can be employed, including sorbitol, propylene glycol, polyethylene glycol, glycerol or mixtures thereof, for example.

[0051] The formulations provided herein may also comprise approximately 0.001% to approximately 90% or approximately 0.001% to approximately 10% of one or more solvents or co-solvents to increase the solubility of any of the components of the present formulation. Solvents or co-solvents for use in this case include, but are not limited to, hydroxylated solvents or other pharmaceutically acceptable polar solvents, such as alcohols, including isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, ether glycol, glycerol and polyoxyethylene alcohols. In another embodiment, the formulations of the present invention can comprise one or more conventional diluents known in the art. The preferred diluent is purified water.

[0052] Tonicity agents (or osmotic adjusting agents) can be added to adjust the isotonicity of the present formulations. Such agents may include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride or mixtures thereof. Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol and dextrose or mixtures thereof. In an alternative embodiment, the present formulation can comprise approximately 0.01% to approximately 10% by weight / weight or 1% to approximately 6% by weight / weight. In an alternative embodiment, the formulations of the present invention are isotonic.

[0053] In certain embodiments here, the formulations of the present invention have a pH of approximately 2.0 to approximately 8.0. Preferably, the pH of the present formulations is from approximately 3.0 to approximately 6.0, preferably the pH is from approximately 3.0 to approximately 4.0. Optionally, the formulations of the present invention contain a pH buffer to maintain the formulation at a desired pH. Buffers suitable for use here include, but are not limited to, citric acid / phosphate, sodium hydroxide, sodium citrate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mclivaine, phosphate , Prideaux- Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2- (N-morpholino) ethanesulfonic acid), BIS-TRIS (bis (2-hydroxyethyl) iminotris (hydroxymethyl) methane ), ADA (N- (2-acetamido) -2-iminodiacetic acid), ACES (N- (carbamoylmethyl) -2-aminoethanesulfonic acid), PIPES (piperazine-N, N'- bis (2-ethanesulfonic acid)), MOPSO (3- (N-morpholino) -2-hydroxypropanesulfonic acid), BIS-TRIS PROPANO (1,3-bis (tris (hydroxy-methyl) methylamino) propane), BES (N, N-bis (2-hydroxyethyl acid) ) -2-aminoethanesulfonic), MOPS (3- (N-morpholino) propanesulfonic acid), TES (N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid), HEPES (N- (2-hydroxyethyl) piperazine-N 'acid - (2-ethanesulfonic), DIPSO (3- (acid of N, N-bis (2-hydroxyethyl) amino) -2-hydroxypropanesulfonic acid), MOBS (4- (N-morpholino) butanesulfonic acid), TAPSO (3- (N-tris (hydroxymethyl) methylamino acid) -2-hydroxypropanesulfonic acid) ), TRIZMAO (tris (hydroxymethylaminomethane), HEPPSO (N- (2-hydroxyethyl) piperazine-N '- (2-hydroxypropanesulfonic acid), POPSO (piperazine-N, N'-bis (2-hydroxypropanesulfonic acid)), TEA ( triethanolamine), EPPS (N- (2-hydroxyethyl) -piperazine-N '- (3-propanesulfonic acid), TRICINE (N-tris (hydroxymethyl) methylglycine), GLY-GLY (glycylglycine), BICINE (N, N-bis (2-hydroxyethyl) glycine), HEPBS (N- (2-hydroxyethyl) piperazine-N '- (4-butanesulfonic acid)), TAPS (N-tris (hydroxymethyl) methyl-3-aminopropanesulfonic acid), AMPD (2- amino-2-methyl-1,3-propanediol) and / or any other buffer known to those skilled in the art.

[0054] In an alternative embodiment, the formulations of the present invention are stable. As used in this case, the stability of formulations provided here refers to the time period at a given temperature that is higher than 80%, 85%, 90% or 95% of the initial amount of the drug substance, for example, fluticasone , is present in the formulation. For example, the formulations provided herein can be stored at between approximately 15 ° C and approximately 30 ° C and remain stable for at least 1, 2, 12, 18, 24 or 36 months. In addition, the formulations may be suitable for administration to a subject who needs them after storage for more than 1.2, 12, 18, 24 or 36 months at 25 °. In addition, in another alternative modality, using Arrhenius kinetics, more than 80% or more than 85% or more than 90% or more than 95% of the initial amount of the drug substance (for example, fluticasone) remain after storage of the formulations for more than 1.2, 12, 18, 24 or 36 months between approximately 15 ° C and approximately 30 ° C.

[0055] As used in this case, the statement that a composition is stable during "long-term storage" means that the composition is suitable for administration to a subject in need of it when an expiration date greater than 1, 2 or 3 months of use time at 25 ° C and more than or equal to 1.2 or 3 years of storage time at 5 ° C. In certain embodiments in this case, using Arrhenius kinetics,> 80% or> 85% or> 90% or> 95% of estimated bronchodilating agent remains after such storage.

[0056] The formulations of the present invention can be administered in a variety of ways, preferably by inhalation. For example, the present formulations can be administered to an individual who needs them by means of an inhaler, for example, a metered dose inhaler or a dry powder inhaler, an insufflator, a nebulizer or any other conventionally known method of administration of inhalable drugs. Preferably, the formulation of the present invention is administered by nebulization. In an alternative embodiment, the formulations of the present invention can be administered by means of a pressurized aerosol comprising, separately, a hypertension reducing agent or a salt or an ester thereof with at least one suitable propellant or with a surfactant or with a mixture of surfactants. Any conventionally known propellant can be used.

[0057] In certain embodiments, the compositions are administered by nebulization. The administration of a nebulized aerosol is preferred over the use of dry powders for inhalation in certain populations of subjects, including pediatric and geriatric groups.

[0058] Combinations containing a composition provided here and a nebulizer are also provided here. The combinations can be packaged as kits, which optionally contain other components, including instructions for using the nebulizer. Any nebulizer is considered for use in the kits and methods provided here. In particular, nebulizers for use in this case nebulize liquid formulations, including the compositions provided herein, which do not contain propellant. The nebulizer can produce nebulized fog by any method known to those skilled in the art, which includes, but is not limited to, compressed air, ultrasonic waves or vibration. The nebulizer may also have an internal baffle. The internal baffle, together with the nebulizer housing, selectively removes large droplets from the impact mist and allows the droplets to return to the reservoir. The fine aerosol droplets thus produced are drawn into the lung by inhaling air / oxygen.

[0059] As used in this case, a nebulized solution refers to a solution that is dispersed in air to form an aerosol. Thus, a nebulized solution is a particular form of an aerosol. As used in this case, a nebulizer is an instrument that is capable of generating a very fine liquid droplet for inhalation into the lung. Within this instrument, the liquid or nebulizer solution is atomized in a mist of droplets with a wide distribution of size by methods known to those skilled in the art, including, but not limited to, compressed air, ultrasonic waves or an orifice in vibration. Nebulizers may also contain, for example, a baffle that, together with the instrument housing, selectively removes large droplets from the mist by impact. Thus, the inhaled mist in the lung contains fine aerosol droplets.

[0060] In an alternative embodiment, the compositions provided herein are intended for administration to a subject in need of such nebulizer treatment. Nebulizers that nebulize liquid formulations that do not contain propellant are suitable for use with the compositions provided herein. Nebulizers are available for example, from Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex. UK), Healthdyne, Vital Signs, Baxter. Allied Health Care, Invacare. Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens. Aerogen, Mountain Medical. Aerosol Medical Ltd. (Colchester, Essex. UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplies (London, UK). Intersurgical (Berkshire, UK), Lifecare Hospital Supplies (Leies, UK), Medic-Aid Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK) and many others.

[0061] Nebulizers for use in this case include, but are not limited to, jet nebulizers (optionally sold with compressors), ultrasonic nebulizers and others; Examples of jet stabilizers for use in this case include Pari LC plus / ProNeb, Pari LC plus / ProNeb Turbo, Pari LC plus / Dura Neb 1000 & 2000, Pari LC plus / Walkhaler, Pari LC plus / Pari Master, Pari LC star, Omron CompAir XL Portable Nebulizer System (NE-CI8 and JetAir Disposable Nebulizer), Omron CompAir Elite Compressor Nebulizer System (NE-C21 and Reusable Nebulizer Elite Air), Pari LC Plus or Pari LC Star nebulizer with Proneb Ultra, Pulmo-aide, Pulmo-aide LT, Portable Pulmo-aide, Invacare Passport, Healthdyne 626 Inspiration, Pulmo-Neb Traverier, DeVilbiss 646, Whisper Jet, Acorn 11, Misty-Neb, Allied aerosol, Schuco Home Care, Lexan Plasic Pocet Neb, SideStream Hand e Held Neb, Mobil Mist, Up-Draft, Up-Draft 11, T Up-Draft, ISO-NEB, AVA-NEB, Micro Mist and PulmoMate. Examples of ultrasonic nebulizers for use in this case include MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 ultrasonic Neb, 51 1 0 Ultrasonic Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Luminscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer and MABISMist H and Held Ultrasonic Nebulizer. Other nebulizers for use in this case include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, Aerodose Inhaler, and AeroEclipse Breath Actuated Nebulizer.

[0062] Pharmaceutical compositions containing a hypertension reducing agent for administration via nebulization are provided. The compositions can be filtered sterile and placed in small vials, including small unit dose vials that provide sterile unit dose formulations that are used in a nebulizer and properly nebulized. Each small unit dose vial can be sterile and properly nebulized without contaminating other small vials or the next dose.

[0063] Small vials for unit dose can be formed in a form-fill-seal machine or by any other suitable method known to those skilled in the art. The small bottles can be made of plastic materials that are used properly in these processes. For example, plastic materials for preparing small unit dose vials include, but are not limited to, low density polyethylene, high density polyethylene, polypropylene and polyesters. In one embodiment, the plastic material is low density polyethylene.

[0064] In another alternative embodiment, the system of the present invention comprises one or more application containers pre-loaded with approximately 0.1 to approximately 5.0 ml, or approximately 0.5 ml_ to approximately 5.0 ml, or approximately 1.0 ml to approximately 5.0 ml; or approximately 0.1 ml_ to approximately 3.0 ml, or approximately 0.1 ml_ to approximately 2.0 ml, or approximately 0.5 ml_ to approximately 2.0 ml, or approximately 1 ml, or approximately 1.5 ml , or approximately 2.0 ml, or approximately 2.5 ml, or approximately 3.0 ml, or approximately 3.5 ml, or approximately 4.0 ml, or approximately 4.5 ml, or approximately 5.0 ml, or approximately 0.1 ml_ to approximately 2.25 ml, or approximately 1.0 ml_ to approximately 2.0 ml, or approximately 2.0 ml_ to approximately 2.4 ml_ of a premixed, pre-mixed aqueous solution for inhalation measure comprising only a unit dose of a therapeutically effective amount of one or more pulmonary hypertension reducing agents.

[0065] Drugs administered by nebulization could play a major role in the treatment of pulmonary hypertension. However, a possible drawback of nebulizer therapy is the number of times it must be performed each day and the length of time that each treatment takes. For example, it may be necessary for an individual to receive 4 doses of nebulized inhalation solution. In some cases, each nebulizer treatment takes approximately 15 minutes or more to apply a 2.5 mL load volume of a bronchodilator, although the time period may vary depending on the model of nebulizer used. The time requirements for nebulizer therapy can be bothersome and cause individuals to miss the required dosages during the day. The impact of not following the prescribed dosage regimen could compromise the individual's condition.

[0066] In an alternative embodiment, the volume of one or more inhalation solutions with pulmonary hypertension reducing agents is approximately 0.1 mL to approximately 2.25 mL or approximately 0.1 mL to approximately 2 mL or approximately 1 mL up to approximately 2 ml or approximately 1.5 ml to approximately 2 ml, preferably approximately 1 ml, approximately 1.5 ml, approximately 2.0 ml or approximately 2.25 ml although no clinical or other experiments have been carried out on these filling volumes , it is believed that such volumes are more advantageous in relation to the volume solutions to fill the nebulizer (for example, 2.5 mL or 3.0 mL of cargo volume) because they will allow the individual to receive more medication (for example, example, one or more pulmonary hypertension reducing agents) in less time during each nebulization treatment. In addition, it is believed that the loading volumes of the present invention will minimize common complications of manipulation with nebulizer therapy and may prolong the life of the nebulizer.

[0067] In an alternative embodiment, the load volumes of the present invention can reduce the time period of each nebulization treatment by at least 20%, 30%, 40%, 50%, 60%, 70% or 80% or more in relation to treatments with conventional nebulizer (for example, 2.5 mL or 3 mL of cargo volume). In another alternative embodiment, the loading volumes of the present invention can reduce the nebulizer treatment to approximately 12, 10, 9, 8, 6, 5, 4, 3 minutes, or less compared to conventional nebulizer treatments (for example , 2.5 mL or 3.0 mL of cargo volume). Reducing the time to complete treatment means that individuals will be more likely to accept the prescribed dosage regimen and achieve optimal benefit from the prescribed medication.

[0068] Another possible drawback of conventional nebulizer treatments is the loss of medication during administration. Conventional nebulizer solutions comprise approximately 2.5 mL of inhalation solution charge volume, or more. For example, when nebulization is performed, an inhalation solution comprising 2.5 ml or more, approximately 0.7 ml of the solution remains in the nebulizer system after treatment, although the amount may vary depending on the model of nebulizer used. In these cases, the individual is not receiving the prescribed dosage or the optimal dosage of the inhalation medication. For example, in one day, because of the residual medication that remains in the nebulizer system after each treatment, an individual fails to receive approximately 2.1 mL or more of the prescribed daily amount of medication.

[0069] It is believed that the loading volumes of one or more solutions for inhalation of pulmonary hypertension reducing agent of the present invention will result in smaller amounts of solution remaining in the nebulizer system after treatment, when compared to conventional solutions for inhalation (for example, 2.5 mL or 3 mL of charge volume). Less solution left in the nebulizer system means more medication (for example, one or more pulmonary hypertension reducing agents) administered to the individual during each treatment. In an alternative embodiment, the amount of solution remaining in the nebulizer system after each treatment can be less than 0.50 ml or less than 0.30 ml or less than 0.20 ml or less than 0.10 ml or less than 0.05 ml of one or more solutions for inhaling pulmonary hypertension reducing agents of the present invention, for example, a solution for inhalation comprising 2.5 mg of albuterol and 0.5 mg of ipratropium bromide.

[0070] The important factors for effective nebulizer treatment are taking a deep breath to ensure that the medication penetrates deeply into the lungs and maintaining regular breathing to ensure good medication retention in the lungs. It is believed that the administration of approximately 0.1 ml to approximately 2.0 ml of the volume of the inhalation solution into a nebulizer, for example, will optimize the therapeutic effect of the individual's deep inspiration efforts during the treatment and will optimize the therapeutic effect of the individual's breathing maintenance efforts in the same way. This is due to the shorter treatment period and the higher concentration of one or more of the pulmonary hypertension reducing agents in the solution.

[0071] Consequently, in an alternative modality, the present invention is a method to facilitate patient care, reducing medication errors, reducing the treatment time in the nebulizer, improving the efficiency and effectiveness of nebulizer therapy or improving the therapeutic acceptance of an individual suffering from pulmonary hypertension. In an alternative embodiment, such a method may comprise the step of placing approximately 0.1 ml to approximately 2.0 ml of the inhalation solutions of the present invention in a nebulizer chamber. The nebulizer having a mouthpiece or a face mask associated with the nebulizer chamber. The mouthpiece or face mask is positioned in close proximity to the individual's mouth or face. The inhalation solution can be passed in a mist from the nebulizer chamber through the mouthpiece or face mask for the individual while the individual breathes through the mouthpiece or face mask. The individual continues to breathe through the mouthpiece or face mask until the nebulization treatment has ended. This can take approximately 12,11,10,9,8,7, 6, 5,4 or 3 minutes. In an alternative embodiment, the nebulizer treatment is terminated when at least substantially all of the mist is removed from the nebulizer chamber. This can take approximately 12, 11, 10,9,8,7, 6, 5, 4, or 3 minutes. In an alternative embodiment of the present invention, the dose of the inhalation solution in each of one or more containers can be administered 1, 2, 3, 4, 5, 6, 7 or 8 times per day by nebulization.

[0072] In another alternative embodiment, the system / kit of the present invention may further comprise a label indicating that the inhalation solution can be used to relieve bronchospasm associated with chronic obstructive pulmonary disease. In an alternative embodiment, the label may comprise indications comprising efficacy, dosage, administration, contraindication and adverse reaction data pertaining to the inhalation solution in each of one or more containers. The contraindication data may comprise data indicating that the inhalation solution in each of one or more containers is contraindicated for humans who are hypersensitive to any of the ingredients contained in the inhalation solution.

[0073] The dosage and administration data may also comprise data indicating that the recommended dose of the inhalation solution in each of one or more containers can be administered 1,2,3, 4, 5, 6, 7 or 8 times a day by nebulization.

[0074] In an alternative embodiment, the present invention also comprises a device for use in relieving symptoms associated with pulmonary hypertension, including bronchospasm. Such a device may take the form of a label, written instructions or any other form that incorporates evidence. The device may comprise evidence to show that a patient suffering from symptoms associated with pulmonary hypertension can be treated with at least one pre-packaged, sterile, pre-mixed and / or BAC-free inhalation solution comprising a unit dose of one therapeutically effective amount of one or more pulmonary hypertension reducing agents in a single small bottle. The inhalation solution being suitable for nebulization in a nebulizer. The device may also comprise evidence that provides instructions for using the inhalation solution to treat said symptoms in patients.

[0075] The inhalation formulations of the present invention can be used to treat "pulmonary hypertension" (as that term is defined here) including but not limited to primary pulmonary hypertension, secondary hypertension and classes I - IV as shown in Table 1, among others. For example, the formulations of the present invention can be used to treat or ameliorate one or more of the following symptoms of pulmonary hypertension associated with disorders of the respiratory system and / or hypoxemia: chronic obstructive pulmonary disease, interstitial lung disease, disturbed sleep breathing ; disorders of alveolar hypoventilation; chronic exposure to high altitudes; neonatal lung disease and alveolar capillary dysplasia. The information in Table 1 is presented for illustrative purposes only. This is not intended to limit the scope of the invention. TABLE 1

[0076] The formulations of the present invention can comprise one or more pulmonary hypertension reducing agents. In one embodiment, the formulation of the present invention comprises one of an ACEI, ARB, a beta-blocker, a calcium channel blocker, a vasodilator or any combination thereof. Such a combination can explicitly exclude in this case any of the reducing agents of pulmonary hypertension. In an alternative embodiment, the formulation of the present invention comprises an ACEI in combination with an ARB, a beta-blocker, a calcium channel blocker or a vasodilator. In another embodiment, the formulation of the present invention comprises an ARB in combination with a beta-blocker, a calcium channel blocker or with a vasodilator. In yet another embodiment, the formulation of the present invention comprises a beta-blocker in combination with a calcium channel blocker or a vasodilator. In yet another embodiment, the formulation of the present invention comprises a calcium channel blocker and a vasodilator. In an alternative embodiment in this case, the present invention comprises any combination of at least three ACEIs, ARBs, beta-blockers, calcium channel blockers or vasodilators.

[0077] Additionally, the formulations of the present invention can be administered together with one or more other drugs or therapies. For example, the present formulations can be administered with an anticoagulant such as warfarin (Coumadin), which is recommended to prevent thrombosis and has been shown to prolong life in patients with primary pulmonary hypertension. Pulmonary hypertension patients are prone to thromboembolism because of slow pulmonary blood flow, dilated right heart chambers, venous insufficiency and relative physical inactivity.

[0078] Additionally, the formulations of the present invention can be administered in combination with or in combination with inotropic agents such as digoxin (Lanoxin), which has been shown to produce acute hemodynamic effects in patients with right ventricular failure and primary pulmonary hypertension. Inotropic drugs administered parenterally in the short term can also be administered with the formulations of the present invention. In addition, since hypoxia is a potent pulmonary vasoconstrictor, the formulations of the present invention can be administered in combination with supplementary low-flow oxygen therapy, which is known to prolong survival in hypoxemic patients.

[0079] In addition, the formulations of the present invention can be administered in combination with a low-salt diet and / or diuretics, which are useful in reducing volume overload in patients with pulmonary hypertension and right ventricular failure. However, excessive diuresis and further reduction in cardiac output should be avoided.

[0080] The present invention is also directed to a method of treating pulmonary hypertension in a mammal including animals and humans. In one embodiment, a therapeutically effective amount of a hypertension-reducing pharmaceutical agent is administered to a mammal in need thereof. In an alternative embodiment, the formulation of the present invention is pre-measured, pre-mixed and pre-packaged. In one embodiment, the formulation of the method of the present invention comprises from approximately 0.01 mg / ml to approximately 20 mg / ml of at least one of an ACEI, an ARB, a beta-blocker, a calcium channel blocker or a vasodilator or any combination thereof. In an alternative embodiment, the formulation is sterile and / or stable. In another embodiment, the formulation is free of preservatives.

[0081] In another alternative embodiment, the method of the present invention comprises the step of administering to a mammal in need of a solution for inhalation comprising a therapeutically effective amount of a hypertension-reducing pharmaceutical agent, wherein the solution for inhalation is administered via a nebulizer, such a nebulizer including, but not limited to, a jet nebulizer, an ultrasonic nebulizer and a breath-driven nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate air flow, the nebulizer being equipped with a mouthpiece or a suitable face mask.

[0082] The present invention is also directed to a system and / or kit for treating pulmonary hypertension in a mammal. In one embodiment, the kit of the present invention comprises a formulation comprising a therapeutically effective amount of a pulmonary hypertension reducing agent. In an alternative embodiment, the formulation is pre-measured, pre-mixed and / or pre-packaged. Preferably, the inhalation solution is sterile.

[0083] The system and / or kit of the present invention can also include instructions indicated to facilitate acceptance by the user. The instructions, as used in this case, refer to any label, insert, etc. and may be positioned on one or more surfaces of the packaging material or the instructions may be provided on a separate sheet or any combination thereof. For example, in one embodiment, a system and / or a kit of the present invention comprises instructions for administering the formulations of the present invention. In one embodiment, the instructions indicate that the formulation of the present invention is suitable for the treatment of pulmonary hypertension. Such instructions may also include instructions on dosing, as well as instructions for administration through a nebulizer.

[0084] Non-adherence to therapy with medication against pulmonary hypertension and medication error could be considerable problems. These problems can be significantly reduced by providing patients with pulmonary hypertension with a pre-packaged, pre-mixed, pre-measured amount of an inhalable formulation comprising one or more pulmonary hypertension reducing agents. Providing these compounds in this way makes therapy for pulmonary hypertension simple because it increases convenience and eliminates confusion in preparing appropriate dosages.

[0085] In an alternative embodiment, the present invention can avoid the problems mentioned above by providing therapeutically effective amounts of one or more pulmonary hypertension reducing agents in prepackaged, pre-mixed, pre-measured and / or unit dosage amounts. In an alternative embodiment, the present invention comprises one or more pre-loaded containers. One or more containers each comprise a single unit dose of an aqueous solution comprising a therapeutically effective amount of one or more pulmonary hypertension reducing agents. Providing the inhalation solution in such a way eliminates the need to dilute or mix such medications to obtain appropriate dosages for treatment. In addition, no special pharmaceutical preparation is required, thereby reducing the chance of medication errors. In addition, there is a lower risk of reciprocal contamination and less waste of medication when providing an inhaled solution in a pre-mixed form, ready to use.

[0086] Other features of the present invention include better acceptance by the user and quality of life compared to conventional treatments for pulmonary hypertension. Although the level of acceptance of any treatment for pulmonary hypertension depends in part on the user's motivation and the individual's expertise in applying the treatment, nevertheless the acceptance can be improved by control factors such as the ease with which it can be administered. treatment, as well as the desirability of receiving treatment.

[0087] The present invention provides a convenient, fast and reliable treatment for pulmonary hypertension and clearly represents an improvement over traditional treatments for pulmonary hypertension. In addition, the present invention is designed to facilitate acceptance by the user by providing one or more application containers comprising a pre-mixed, pre-measured inhalation solution comprising a simple unit dose of an effective amount of one or more reducing agents. pulmonary hypertension for the treatment of pulmonary hypertension. Such containers can be used in a method of treating pulmonary hypertension or the containers can be incorporated into a system and / or kit for treating it.

[0088] In another embodiment, the present invention provides a system and / or kit for organizing and storing one or more pre-filled application containers, each container comprising a pre-mixed, pre-mixed inhalation solution. The inhalation solution comprising a single unit dose of a therapeutically effective amount of one or more pulmonary hypertension reducing agents. Such a system and / or kit can provide such containers in a pre-packaged form. One or more containers can be comprised of plastic which include, but are not limited to, a semipermeable plastic such as LDPE. The container can also comprise a Twist-Flex® top, such a top comprising a handle as an easy-to-hold projection such that the container can be opened, for example, by manually twisting the projection. The Twist-Flex® top is advantageous in that it allows easy application of the solution, avoids spillage and eliminates the need to open the container by cutting or tearing the top or similar, thereby reducing reciprocal contamination. In an alternative embodiment, the design of the container is substantially in accordance with those designs illustrated in U.S. Patent Des. No. 317,715; 296,869; 289,609 or 275,732, which are incorporated herein by reference. One or more of the semipermeable containers for single unit dose can be prepackaged in an aluminum foil pouch, such that the foil provides a protective barrier against environmental contaminants and against light. Such a barrier improves the shelf life of the inhalation solution.

[0089] In another alternative embodiment, the present invention comprises a pre-packaged inhalation system and / or kit suitable for patients suffering from pulmonary hypertension. Such a pre-packaged system and / or kit comprising: (a) one or more simple unit dosages of a therapeutically effective amount of one or more pulmonary hypertension reducing agents; (b) instructions for administration for the use of said unit dose as a treatment for pulmonary hypertension; and (c) a container for application pre-loaded with one or more unit doses of one or more pulmonary hypertension reducing agents.

[0090] The formulations of the present invention can be manufactured in any conventional manner by thoroughly mixing the ingredients described herein at room or elevated temperatures to achieve solubility of the ingredients when appropriate.

[0091] Articles of manufacture, containing packaging material, a formulation provided herein, may be useful for treating, preventing or ameliorating one or more symptoms of diseases or disorders associated with pulmonary hypertension, such articles of manufacture may also comprise a label which indicates that the composition is used to treat, prevent or ameliorate one or more symptoms of diseases or disorders associated with pulmonary hypertension.

[0092] In an alternative embodiment, the manufacturing articles provided here contain packaging materials. Packaging materials for use in the packaging of pharmaceutical products are well known to those skilled in the art. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, vials, tubes, inhalers, pumps, bags, small vials, containers, syringes, bottles and any packaging material suitable for a selected formulation and mode of administration and desired treatment.

V. EXAMPLES

[0093] Examples 1-4 here are prophetic examples provided to illustrate, but not to limit the formulations and processes of the present invention. They are presented with the understanding that changes can be made and may need to be made for a specific composition to obtain or optimize the formulation. Such modifications to the following prophetic examples, if necessary, are normal and understandable to those skilled in the art and should not be used to limit the invention.

[0094] It is believed that prophetic examples 1-4 would be suitable for administration through nebulization to an individual suffering from pulmonary hypertension. The formulations can be sterile. The purpose of these formulations is to provide localized application of a pulmonary hypertension reducing agent to a mammal (for example, humans) who need it. EXAMPLE 1

[0095] Example 1 is a prophetic example of a formulation comprising ACEI enalapril. Sodium chloride can be added to the solution to adjust tonicity and sodium hydroxide can be added to the solution to adjust the pH of the solution. The solution of Example 1 can be obtained by methods known to the person skilled in the art. EXAMPLE 2

[0096] Example 2 is a prophetic example of a formulation comprising the beta-blocker atenolol. Sodium chloride can be added to the solution to adjust tonicity and sodium hydroxide and citric acid are added to adjust the pH of the solution. The solution of Example 2 can be obtained by methods known to those skilled in the art. EXAMPLE 3

[0097] Example 3 is a prophetic example of a formulation comprising the epoprostenol dilating vessel. Span 85 can be added as an emulsifier. The suspension of Example 3 can be obtained by methods known to those skilled in the art. EXAMPLE 4

[0098] Example 4 is a prophetic example of a formulation comprising the vasodilator epoprostenol. Sodium chloride can be added to the solution to adjust tonicity and sodium hydroxide and citric acid are added to adjust the pH of the solution. The solution of Example 4 can be obtained by methods known to those skilled in the art.

[0099] The Figures and annexes here are presented for purposes of illustration only. They are not intended to limit the scope of the invention. In addition, it should be understood that several changes and modifications to the modality described here are evident to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its pertinent advantages. It is therefore intended that such changes and modifications are covered by the appended claims. Furthermore, the invention can suitably comprise, consist of or consist essentially of the elements or steps described herein. Furthermore, the invention adequately described herein can comprise or be carried out in the absence of any element or step that is not specifically disclosed herein. In addition, one or more steps described here can be performed simultaneously with another step.

Claims (3)

1. Inhalable formulation for the treatment of pulmonary hypertension, characterized by the fact that it comprises: 0.2 mg / mL to 10 mg / mL of Enalaprilat (s-1- [N- (1-carboxy-3-phenylpropyl) -L- alanyl] -L-praline dehydrated, 2.0 mg / mL to 10 mg / L sodium chloride, sodium hydroxide, and water, the said formulation being suitable for administration by nebulization to a mammal in need of the same. 2. Formulation according to claim 1, characterized by the fact that it is a sterile aqueous suspension. 3. Formulation according to claim 1 or 2, characterized by the fact that it comprises a preservative.